Straightforward and Clean Ultrasound-Promoted Synthesis of 2-(4,5-Dihydro-1H-pyrazol-1-yl)pyrimidines

Grupo de Pesquisa em Síntese e Caracterização Molecular, Faculdade de Ciências Exatas e Tecnologia, Universidade Federal da Grande Dourados, R. João Rosa Góes, 1761, 79825-070 Dourados-MS, Brazil Departamento de Química, Universidade Federal de Santa Maria, Av. Roraima, 1000, 97105-900 Santa Maria-RS, Brazil Departamento de Ciências Exatas e da Terra, Universidade Federal de São Paulo, Rua Prof. Artur Riedel, 275, 09972-270 Diadema-SP, Brazil Departamento de Química Fundamental, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, 05508-000 São Paulo-SP, Brazil Instituto de Química e Geociências, Universidade Federal de Pelotas, Campus Universitário, s/n, 96010-900 Pelotas-RS, Brazil


Introduction
In the past years, significant efforts have been made in preparing 2-(pyrazol-1-yl)pyrimidines derivatives and several studies have pointed such compounds as promising bioactive molecules.In this direction, epirizole has been therapeutically applied as a nonsteroidal anti-inflammatory and analgesic agent in Japan. 1 Additionally, 2-(pyrazol-1-yl)pyrimidine derivatives have shown ulcerogenicity and protective activity against lesions induced by acidic anti-inflammatory agents in the rat stomach, 2 as well as fungicidal, 3 herbicidal, 4 and cardiotonic activities. 5ecently, several 2-(pyrazol-1-yl)pyrimidines were prepared and they showed efficacy as A 2A adenosine receptor antagonists for the treatment of Parkinson's disease. 6,7oreover, structurally related 4-(pyrazol-4-yl)pyrimidines were recently identified as potent c-Jun N-terminal kinase (JNK) 8 and cyclin-dependent kinase (CDK) 9 protein inhibitors with potential application in the treatment of type 2 diabetes and human neoplasia, respectively.In the field of material chemistry, pyrazolylpyrimidines have attracted attention due to potential application as ligands for the synthesis of transition metal complexes 10 which manifest luminescence 11 and catalytic activity. 12-(Pyrazol-1-yl)pyrimidines are generally synthesized by the cyclocondensation of 1,3-dieletrophiles and 1-carboxamidino-pyrazoles 13,14 or 2-hidrazinopyrimidines 15 in [3+3] or [3+2] processes, respectively.One-pot cyclocondensation of aminoguanidine bicarbonate with two equivalents of 4-alkoxyvinyl-trifluoromethyl ketones afforded trifluoromethyl-substituted 2-(pyrazol-1-yl) pyrimidines in moderate to good yields in long reaction times (4-8 h) in ethanol under reflux.16 Similarly, tetraarylsubstituted 2-(pyrazol-1-yl)pyrimidines were obtained in moderate yields when chalcones were used as the 1,3-dielectrophile in the cyclocondensation reaction Vol.26, No. 6, 2015   with aminoguanidine bicarbonate under essentially the same conditions.17 The disadvantage of using such onepot reaction is that both pyrazole and pyrimidine rings substituents are the same.
7][28][29] The use of ultrasound to accelerate reactions has proven to be a particularly important tool for reaching the green chemistry goals of minimization of waste and reduction of energy requirements. 30In concern, several studies clearly showed the importance of taking advantage of the unique features of ultrasound-assisted reactions in the synthesis of heterocyclic compounds. 31,32n this context, we report here a clean and straightforward procedure to prepare a series of novel 2-(4,5-dihydro-1Hpyrazol-1-yl)pyrimidines under ultrasonic irradiation using ethanol as a green solvent in short reaction times and dispensing the use of complicated work-up.

Results and Discussion
The building blocks 1-carboxamidino-4,5-dihydro-1H-pyrazoles 1a-k and 4-alkoxyvinyl-trifluoromethyl ketones 2 and 3 were prepared according to previously reported procedures. 22,33The novel products 4a-k and 5a were obtained in good yields by the ultrasound-promoted cyclocondensation reaction between compounds 1a-k and α,β-unsaturated ketones 2 or 3 in a molar ratio of 1:1 in the presence of 0.5 eq of KOH (Table 1).The reaction time was determined by monitoring the consumption of the starting materials by thin layer chromatography (TLC).The isolation of the pure products was achieved after keeping the crude reaction mixtures in a refrigerator followed by filtration of the white solid precipitates formed.The scope of the methodology is illustrated by the preparation of a series of twelve compounds.
A mixture of two products was detected by gas chromatography (GC) when 1-carboxamidino-4,5-dihydro-1H-pyrazole 1a and 4-alkoxyvinyl-trifluoromethyl ketone 3 were allowed to react using ethanol as solvent.The mass spectra of these products showed that they correspond to the desired methyl ester derivative and the ethyl ester derivative formed as coproduct due to a partial parallel transesterification reaction.In order to circumvent this mixture formation, methanol was used as solvent for the preparation of the pyrazolylpyrimidine 5a, exclusively.
All the synthesized compounds were fully characterized by 1 H and 13 C nuclear magnetic resonance (NMR), infrared (IR) spectroscopy and high-resolution mass spectrometry (HRMS) or elemental analysis.The IR, 1 H and 13 C NMR spectra of products showed sets of signals corresponding to the proposed structures and in agreement with data reported in the literature for analogous molecules. 14The structures were confirmed by elemental analysis or HRMS.
In order to show the beneficial effect of the ultrasonic irradiation in our sonochemical synthesis, we performed two control experiments in the absence of ultrasonic irradiation: first, the starting materials 1a and 2 were allowed to react for 60 min in 2:2:1 molar ratio with KOH under room temperature in ethanol; then, the reaction was carried out under reflux for 24 h.Under the former silent condition the formation of product 4a was not observed.The reaction conducted under reflux furnished a mixture of 1a and 4a in approximately 1:1 molar ratio, as determined by 1 H NMR.
Although the mechanism of the ultrasound-promoted cyclocondensation reaction was not yet experimentally established, a possible explanation is proposed in Scheme 1.Initially, the reaction involves the attack from 1-carboxamidino-4,5-dihydro-1H-pyrazoles 1 to the β-position of 4-alkoxyvinyl-trifluoromethyl ketones 2, 3, leading to intermediates I which are in equilibrium with II.In the next step, intermediates II eliminate MeOH to give intermediates III.Then an intramolecular nucleophilic attack of imino nitrogen to the carbonyl leads to intermediates IV, which are in equilibrium with V.
Finally, the elimination of water from V occurs to give the compounds 4, 5.

Conclusions
In summary, we developed an efficient, clean and facile method for the preparation of a series of 2-(4,5-dihydro-1H-pyrazol-1-yl)pyrimidines.Our sonochemical method offers several advantages over existing methods, including improved yields, cleaner reactions, simple work-up and very short reaction times, which makes it an useful and environmentally attractive strategy for the synthesis of pyrazolylpyrimidines derivatives, compounds with promising bioactivity.

Table 1 .
Reaction conditions, melting points and yields of synthesized compounds 4a-k and 5a a Yield of the isolated product; b this reaction was carried out using methanol as solvent.